CA2323015A1 - Remedies for aids - Google Patents
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- CA2323015A1 CA2323015A1 CA002323015A CA2323015A CA2323015A1 CA 2323015 A1 CA2323015 A1 CA 2323015A1 CA 002323015 A CA002323015 A CA 002323015A CA 2323015 A CA2323015 A CA 2323015A CA 2323015 A1 CA2323015 A1 CA 2323015A1
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- tubercle bacillus
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- aids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- General Health & Medical Sciences (AREA)
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Abstract
Remedies for AIDS containing as the active ingredients (a) a composition mainly comprising a polysaccharide originating in a hot water extract of human tubercle bacillus, and (b) an anti-HIV agent of the nucleoside type. In these remedies, the composition (a) enhances the therapeutic effect of the anti-HIV agent on AIDS.
Description
SPECIFICATIOIN
REMEDIES FOR AIDS
FIELD OF THE INVETION
The present invention relates to remedies for AIDS
(Acquired Immunodeficiency Syndrome).
Background Art AIDS is a disease caused by HIV (Human Immunodeficiency Virus) infection, and the number of patients suffering AIDS has markedly increased in recent years. In therapy for AIDS, there have been used nucleoside-type anti-HIV agents such as Zidovudine (Azidothymidine, AZT) and Didanosine (ddI).
However, these conventional anti-HIV agents do not provide sufficient therapeutic effect and thus development of new AIDS therapeutic means is demanded.
DISCLOSURE OF THE INVENTION
The present inventors have conducted careful studies in an attempt to improve the therapeutic effect of nucleoside-type anti-HIV agents on AIDS patients. They have found that the combined use of a hot water extract of tubercle bacillus and a nucleoside-type anti-HIV agent dramatically improves the mortality of AIDS patients as compared with the case in which the anti-HIV agent alone is administered, leading to completion of the invention.
Accordingly, the present invention provides remedies for AIDS, which comprise as active ingredients (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV agent.
The present invention also provides enhancer drugs for improving the therapeutic effect of a nucleoside-type anti-HIV agent on AIDS, which comprise as an active ingredient (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus.
The present invention further provides use of (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus, for the manufacture of enhancer drugs which improve therapeutic effect of a nucleoside-type anti-HIV
agent on AIDS.
The present invention still further provides use of (a) a composition containing as the primary ingredient a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV agent, for the manufacture of remedies for AIDS.
The present invention yet further provides a method for treating AIDS, which comprises administering to an HIV-infected patient (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV
agent.
REMEDIES FOR AIDS
FIELD OF THE INVETION
The present invention relates to remedies for AIDS
(Acquired Immunodeficiency Syndrome).
Background Art AIDS is a disease caused by HIV (Human Immunodeficiency Virus) infection, and the number of patients suffering AIDS has markedly increased in recent years. In therapy for AIDS, there have been used nucleoside-type anti-HIV agents such as Zidovudine (Azidothymidine, AZT) and Didanosine (ddI).
However, these conventional anti-HIV agents do not provide sufficient therapeutic effect and thus development of new AIDS therapeutic means is demanded.
DISCLOSURE OF THE INVENTION
The present inventors have conducted careful studies in an attempt to improve the therapeutic effect of nucleoside-type anti-HIV agents on AIDS patients. They have found that the combined use of a hot water extract of tubercle bacillus and a nucleoside-type anti-HIV agent dramatically improves the mortality of AIDS patients as compared with the case in which the anti-HIV agent alone is administered, leading to completion of the invention.
Accordingly, the present invention provides remedies for AIDS, which comprise as active ingredients (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV agent.
The present invention also provides enhancer drugs for improving the therapeutic effect of a nucleoside-type anti-HIV agent on AIDS, which comprise as an active ingredient (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus.
The present invention further provides use of (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus, for the manufacture of enhancer drugs which improve therapeutic effect of a nucleoside-type anti-HIV
agent on AIDS.
The present invention still further provides use of (a) a composition containing as the primary ingredient a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV agent, for the manufacture of remedies for AIDS.
The present invention yet further provides a method for treating AIDS, which comprises administering to an HIV-infected patient (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV
agent.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is a graph showing the chronological change of the survival rate of mice suffering murine AIDS (MAIDS).
BEST MODE FOR CARRYING OUT THE INVENTION
The composition (a); i.e., a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus, which is used in the present invention is known to have excellent recovery action against reduction of white blood cells caused by radiotherapy for cancers (see among others "The Clinical Report (Basic and Clinical Report)," 24(4), 1973 (1990) and "Nippon Igaku Hoshasen Gakkai Zasshi," 50(8), 993(1990)).
However, the effect of this composition (a) on AIDS is still unknown.
The composition (a) contains a polysaccharide as the primary component. Preferably, the composition (a) contains a polysaccharide whose primary constituents are arabinose, mannose, and glucose, and a small amount of nucleic acid.
The polysaccharide preferably has a molecular weight ranging from 5 x 102 to 5 x 104 as measured by the gel filtration method. The nucleic acid content of composition (a) is preferably 0.05-0.3 wt.~. The composition may contain 1-5 wt.~ of protein. Preferably, the mannose content of the polysaccharide is 10-72 wt.~, the arabinose content 3-30 wt.~, and the glucose content 5-30 wt.~, and particularly preferred are 40-50 wt.~ mannose, 15-25 wt.~ arabinose, and 5-15 wt.~ glucose.
The composition (a) is obtained by purifying a hot-water extract of tubercle bacillus. In more detail, composition (a) is obtained by subjecting cells of tubercle bacillus to extraction with hot water, and the extract is then subjected to protein removal treatment and to treatment for removing polysaccharides having molecular weights of 105 or more. The tubercle bacillus usable in the present invention can be optionally selected from both of human type tubercle bacillus and animal type tubercle bacillus, but human type tubercle bacillus is preferred. Exemplified as the animal type tubercle bacillus are Mycobacterium (M) bovis, M. avium, M. microti, M. kansaii, M. marium and M.
intracellulae. Exemplified as the human type tubercle bacillus are an Aoyama B strain, H37Rv strain and H37Ra strain, particularly the Aoyama B strain being preferred.
Among the aforementioned steps, extraction with hot water is preferably performed with 80-120°C water. Exemplified as the extraction water are water, a saline solution and a NaOH
solution, particularly water being preferred. The protein removal treatment is preferably performed by causing proteins to precipitate by use of a protein precipitant such as sulfosalicylic acid, trichloroacetic acid, or phosphotungstic acid; and subsequently collecting the supernatant. The treatment to remove polysaccharides having molecular weights of 105 or more is preferably performed by causing polysaccharides having high molecular weights to precipitate by use of ethanol, methanol, or acetone in a suitable amount; and subsequently collecting the supernatant.
The component (b); a nucleoside-type anti-HIV agent, is not particularly limited. Preferably exemplified as component (b) are one or more members selected from among Zidovudine (Azidothymidine, AZT), Didanosine (ddI), Zalcitabin (ddC), Stavudine (d4T) and Lamivudime (3TC).
Azidothymidine is particularly preferred.
In the present invention, the composition (a) is preferably administered to a subject in need thereof by injection, particularly preferably subcutaneous injection.
The nucleoside-type anti-HIV agent (b) is preferably administered to a subject in need thereof perorally or by injection, depending on the type of the agent. Examples of the forms of the agent for oral administration include granules, tablets, capsules, and liquids.
The dose of the composition (a) is preferably 2-200 ~g per day, more preferably 20-100 ~g per day, as calculated in terms of the saccharide content of arabinose. The dose of the nucleoside anti-HIV agent (b), which differs in accordance with the type of drug and administration route, is preferably 50-1500 mg per day, more preferably 200-1000 mg per day, in the case of oral administration.
When the composition (a) and the nucleoside-type anti-HIV agent (b) are administered to a subject in need thereof, they are preferably respectively prepared into pharmaceutical compositions suitable for the aforementioned administration routes by incorporating thereto a generally employed, pharmaceutically acceptable carrier. Examples of carriers useful for the preparation of pharmaceutical compositions include vehicles, binders, lubricants, disintegrants, coating agents, emulsifiers, suspensions, solvents, stabilizers, absorption aids, water for injection use, and tonicity agents.
EXAMPLES
The present invention will next be described by way of examples, which should not be construed as limiting the invention thereto.
Referential Example 1 (Preparation of composition (a)):
Mycobacterium tuberculosis strain Aoyama B which had been lyophilized and stored at -20° was subjected to seed culture at 37 ~ 1°C in a Sauton-potato medium~l~. The resultant cells were inoculated to a production medium~2~ and incubated for 5-7 weeks at 37 ~ 1°C. The harvested cells were washed with water for injection use, and to the wet cells was added water for injection use in an amount 20 times that of the weight of the wet cells. The mixture was heated at 100°C for 120 minutes, to thereby obtain an extract. The extract was filtered by use of a 0.45 ~m-membrane filter and concentrated under reduced pressure so that the saccharide content (converted to D-arabinose by the phenol-sulfuric acid method) fell within the range of 4.0-6.0 mg/ml, to thereby obtain a concentrate. Subsequently, in order to remove proteins, one (w/v)~ sulfosalicylic acid was added to the concentrate. The mixture was allowed to stand for 15-20 minutes at a temperature of not higher than 10°C. Precipitates were removed by centrifugal separation (10°C or lower temperature, 1,150 x G, 10 minutes), to thereby recover the supernatant. The protein concentration of the supernatant was not more than 0.30 mg/ml (Lowry method, calculated as tyrosine). The supernatant was further processed to remove sulfosalicylic acid until the content of sulfosalicylic acid was below the detection limit (10 ppm or less, colorimetric method using ferric chloride solution). The resultant solution was concentrated under reduced pressure so that the saccharide content fell within the range of 1.8-2.2 mg/ml, and the concentrate was combined with sodium chloride (0.9 (w/v)~) and cold ethanol whose volume is the same as that of the concentrate. The mixture was allowed to stand for not less than 40 hours at a temperature of not higher than 10°C, and then the precipitates polysaccharide of high molecular weight region were removed by centrifugal separation (10°C or lower temperature, 2,040 x G, 10 minutes). Subsequently, the supernatant was combined with four times the amount of cold ethanol, and the mixture was allowed to stand for not less than 40 hours at a temperature of not higher than 10°C, to thereby recover precipitates. The precipitates were dissolved in water for injection use and after the saccharide content was adjusted to 1.8-2.2 mg/ml, the solution was subjected to filtration by use of a 0.45 ~m membrane filter and to sterilization in an autoclave (121°C, 20 minutes), to thereby prepare a composition (a) solution.
(1) Sauton-potato medium Washed potato slices were soaked in a Sauton medium, followed by sterilization for 15 minutes at 115°C. The resultant material was used as a Sauton-potato medium.
Sauton Medium L-asparagine (monohydrate) 4.0 g Citric acid (monohydrate) 2.0 g Magnesium sulfate (heptahydrate) 0.5 g Potassium monohydrogenphosphate (anhydrite) 0.5 g Ammonium iron citrate 0.05 g Glycerol 60 ml The above ingredients were dissolved in water to make a total volume of 1,000 ml. By use of sodium hydroxide solution, pH was adjusted to 7.0-7.3.
(2) Production medium L-asparagine (monohydrate) 4.0 g Citric acid (monohydrate) 2.0 g Magnesium sulfate (heptahydrate) 0.5 g Potassium monohydrogenphosphate (anhydrite) 0.5 g Ammonium iron citrate 0.05 g Glycerol 60 ml The above ingredients were dissolved in water to make a total volume of 1,000 ml, followed by sterilization in an autoclave (121°C, 20 minutes). By use of sodium hydroxide solution, pH was adjusted to 7.0-7.3.
The physicochemical properties of the composition (a) solution were as follows.
(1) Appearance: Pale yellow clear liquid (2) pH: 4.50-5.30 (3) Protein content: 3.5 wt.% (as an amino acid) in a freeze-dried product (4) Nucleic acid content: 0.1 wt.% in a freeze-dried product (5) Constituent monosaccharides of polysaccharide:
Mannose 43.4 wt.%, Arabinose 18.2 wt.%, and Glucose 10.4 wt.%.
Methods for determining the constituent monosaccharides of polysaccharide: The polysaccharide was hydrolyzed with 2N trifluoroacetic acid for two hours at 100°C, and then subjected to liquid chromatography making use of 2-cyanoacetamide fluoroscein derivative (S. Honda, et al., Anal. Chem., 52, 1079 (1980)).
Test Example:
In accordance with the method described in Antimicrobial Agents and Chemotherapy, Apr. 1990, p.605-609, culture supernatant (0.1 ml) of SC-1 cells infected with LP-BM5 murine leukemia virus was intraperitoneally administered to each of a group of male C57BL/6 mice, to thereby create murine AIDS (MAIDS) mice. AZT and/or composition (a) (a solution obtained in Referential Example 1) were/was administered to the MAIDS mice from the day following the viral infection. AZT was orally administered to each mouse at a dose of 10 mg/kg/day every four days. In the case of composition (a), the solution obtained in Referential Example 1 was intraperitoneally administered to each mouse at a dose of 10 mg/kg/day (calculated as the saccharide content) every two days.
After administration of AZT and/or composition(a), the MAIDS mice were bred for 145 days under observation. The survival rate was determined, and the therapeutic effects of AZT and composition (a) were evaluated. The survival rates after 130 days are summarized in Table 1 and the chronological changes of the survival rates are shown in Fig.
1.
Table 1 Group No. of mice Alive Dead Suvival rate Control 22 8 14 36 Comp. (a) 10 3 7 30 Comp. (a) + AZT 10 8 2 80 Statistical significance between the control group and the treated group in a survival rate was evaluated at day 130 after the viral infection.
*: p=0.027, compared with control (Fisher's exact method).
As shown in Table 1 and Fig. 1, mortality of MAIDS
mice administered with AZT and composition (a) was clearly improved as compared with that of MAIDS mice administered with AZT alone.
INDUSTRIAL APPLICABILITY
As described above, the therapeutic method of the present invention provides remarkably improved therapeutic effect on AIDS patients as compared with the case in which a nucleoside-type anti-HIV agent alone is administered.
Fig. 1 is a graph showing the chronological change of the survival rate of mice suffering murine AIDS (MAIDS).
BEST MODE FOR CARRYING OUT THE INVENTION
The composition (a); i.e., a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus, which is used in the present invention is known to have excellent recovery action against reduction of white blood cells caused by radiotherapy for cancers (see among others "The Clinical Report (Basic and Clinical Report)," 24(4), 1973 (1990) and "Nippon Igaku Hoshasen Gakkai Zasshi," 50(8), 993(1990)).
However, the effect of this composition (a) on AIDS is still unknown.
The composition (a) contains a polysaccharide as the primary component. Preferably, the composition (a) contains a polysaccharide whose primary constituents are arabinose, mannose, and glucose, and a small amount of nucleic acid.
The polysaccharide preferably has a molecular weight ranging from 5 x 102 to 5 x 104 as measured by the gel filtration method. The nucleic acid content of composition (a) is preferably 0.05-0.3 wt.~. The composition may contain 1-5 wt.~ of protein. Preferably, the mannose content of the polysaccharide is 10-72 wt.~, the arabinose content 3-30 wt.~, and the glucose content 5-30 wt.~, and particularly preferred are 40-50 wt.~ mannose, 15-25 wt.~ arabinose, and 5-15 wt.~ glucose.
The composition (a) is obtained by purifying a hot-water extract of tubercle bacillus. In more detail, composition (a) is obtained by subjecting cells of tubercle bacillus to extraction with hot water, and the extract is then subjected to protein removal treatment and to treatment for removing polysaccharides having molecular weights of 105 or more. The tubercle bacillus usable in the present invention can be optionally selected from both of human type tubercle bacillus and animal type tubercle bacillus, but human type tubercle bacillus is preferred. Exemplified as the animal type tubercle bacillus are Mycobacterium (M) bovis, M. avium, M. microti, M. kansaii, M. marium and M.
intracellulae. Exemplified as the human type tubercle bacillus are an Aoyama B strain, H37Rv strain and H37Ra strain, particularly the Aoyama B strain being preferred.
Among the aforementioned steps, extraction with hot water is preferably performed with 80-120°C water. Exemplified as the extraction water are water, a saline solution and a NaOH
solution, particularly water being preferred. The protein removal treatment is preferably performed by causing proteins to precipitate by use of a protein precipitant such as sulfosalicylic acid, trichloroacetic acid, or phosphotungstic acid; and subsequently collecting the supernatant. The treatment to remove polysaccharides having molecular weights of 105 or more is preferably performed by causing polysaccharides having high molecular weights to precipitate by use of ethanol, methanol, or acetone in a suitable amount; and subsequently collecting the supernatant.
The component (b); a nucleoside-type anti-HIV agent, is not particularly limited. Preferably exemplified as component (b) are one or more members selected from among Zidovudine (Azidothymidine, AZT), Didanosine (ddI), Zalcitabin (ddC), Stavudine (d4T) and Lamivudime (3TC).
Azidothymidine is particularly preferred.
In the present invention, the composition (a) is preferably administered to a subject in need thereof by injection, particularly preferably subcutaneous injection.
The nucleoside-type anti-HIV agent (b) is preferably administered to a subject in need thereof perorally or by injection, depending on the type of the agent. Examples of the forms of the agent for oral administration include granules, tablets, capsules, and liquids.
The dose of the composition (a) is preferably 2-200 ~g per day, more preferably 20-100 ~g per day, as calculated in terms of the saccharide content of arabinose. The dose of the nucleoside anti-HIV agent (b), which differs in accordance with the type of drug and administration route, is preferably 50-1500 mg per day, more preferably 200-1000 mg per day, in the case of oral administration.
When the composition (a) and the nucleoside-type anti-HIV agent (b) are administered to a subject in need thereof, they are preferably respectively prepared into pharmaceutical compositions suitable for the aforementioned administration routes by incorporating thereto a generally employed, pharmaceutically acceptable carrier. Examples of carriers useful for the preparation of pharmaceutical compositions include vehicles, binders, lubricants, disintegrants, coating agents, emulsifiers, suspensions, solvents, stabilizers, absorption aids, water for injection use, and tonicity agents.
EXAMPLES
The present invention will next be described by way of examples, which should not be construed as limiting the invention thereto.
Referential Example 1 (Preparation of composition (a)):
Mycobacterium tuberculosis strain Aoyama B which had been lyophilized and stored at -20° was subjected to seed culture at 37 ~ 1°C in a Sauton-potato medium~l~. The resultant cells were inoculated to a production medium~2~ and incubated for 5-7 weeks at 37 ~ 1°C. The harvested cells were washed with water for injection use, and to the wet cells was added water for injection use in an amount 20 times that of the weight of the wet cells. The mixture was heated at 100°C for 120 minutes, to thereby obtain an extract. The extract was filtered by use of a 0.45 ~m-membrane filter and concentrated under reduced pressure so that the saccharide content (converted to D-arabinose by the phenol-sulfuric acid method) fell within the range of 4.0-6.0 mg/ml, to thereby obtain a concentrate. Subsequently, in order to remove proteins, one (w/v)~ sulfosalicylic acid was added to the concentrate. The mixture was allowed to stand for 15-20 minutes at a temperature of not higher than 10°C. Precipitates were removed by centrifugal separation (10°C or lower temperature, 1,150 x G, 10 minutes), to thereby recover the supernatant. The protein concentration of the supernatant was not more than 0.30 mg/ml (Lowry method, calculated as tyrosine). The supernatant was further processed to remove sulfosalicylic acid until the content of sulfosalicylic acid was below the detection limit (10 ppm or less, colorimetric method using ferric chloride solution). The resultant solution was concentrated under reduced pressure so that the saccharide content fell within the range of 1.8-2.2 mg/ml, and the concentrate was combined with sodium chloride (0.9 (w/v)~) and cold ethanol whose volume is the same as that of the concentrate. The mixture was allowed to stand for not less than 40 hours at a temperature of not higher than 10°C, and then the precipitates polysaccharide of high molecular weight region were removed by centrifugal separation (10°C or lower temperature, 2,040 x G, 10 minutes). Subsequently, the supernatant was combined with four times the amount of cold ethanol, and the mixture was allowed to stand for not less than 40 hours at a temperature of not higher than 10°C, to thereby recover precipitates. The precipitates were dissolved in water for injection use and after the saccharide content was adjusted to 1.8-2.2 mg/ml, the solution was subjected to filtration by use of a 0.45 ~m membrane filter and to sterilization in an autoclave (121°C, 20 minutes), to thereby prepare a composition (a) solution.
(1) Sauton-potato medium Washed potato slices were soaked in a Sauton medium, followed by sterilization for 15 minutes at 115°C. The resultant material was used as a Sauton-potato medium.
Sauton Medium L-asparagine (monohydrate) 4.0 g Citric acid (monohydrate) 2.0 g Magnesium sulfate (heptahydrate) 0.5 g Potassium monohydrogenphosphate (anhydrite) 0.5 g Ammonium iron citrate 0.05 g Glycerol 60 ml The above ingredients were dissolved in water to make a total volume of 1,000 ml. By use of sodium hydroxide solution, pH was adjusted to 7.0-7.3.
(2) Production medium L-asparagine (monohydrate) 4.0 g Citric acid (monohydrate) 2.0 g Magnesium sulfate (heptahydrate) 0.5 g Potassium monohydrogenphosphate (anhydrite) 0.5 g Ammonium iron citrate 0.05 g Glycerol 60 ml The above ingredients were dissolved in water to make a total volume of 1,000 ml, followed by sterilization in an autoclave (121°C, 20 minutes). By use of sodium hydroxide solution, pH was adjusted to 7.0-7.3.
The physicochemical properties of the composition (a) solution were as follows.
(1) Appearance: Pale yellow clear liquid (2) pH: 4.50-5.30 (3) Protein content: 3.5 wt.% (as an amino acid) in a freeze-dried product (4) Nucleic acid content: 0.1 wt.% in a freeze-dried product (5) Constituent monosaccharides of polysaccharide:
Mannose 43.4 wt.%, Arabinose 18.2 wt.%, and Glucose 10.4 wt.%.
Methods for determining the constituent monosaccharides of polysaccharide: The polysaccharide was hydrolyzed with 2N trifluoroacetic acid for two hours at 100°C, and then subjected to liquid chromatography making use of 2-cyanoacetamide fluoroscein derivative (S. Honda, et al., Anal. Chem., 52, 1079 (1980)).
Test Example:
In accordance with the method described in Antimicrobial Agents and Chemotherapy, Apr. 1990, p.605-609, culture supernatant (0.1 ml) of SC-1 cells infected with LP-BM5 murine leukemia virus was intraperitoneally administered to each of a group of male C57BL/6 mice, to thereby create murine AIDS (MAIDS) mice. AZT and/or composition (a) (a solution obtained in Referential Example 1) were/was administered to the MAIDS mice from the day following the viral infection. AZT was orally administered to each mouse at a dose of 10 mg/kg/day every four days. In the case of composition (a), the solution obtained in Referential Example 1 was intraperitoneally administered to each mouse at a dose of 10 mg/kg/day (calculated as the saccharide content) every two days.
After administration of AZT and/or composition(a), the MAIDS mice were bred for 145 days under observation. The survival rate was determined, and the therapeutic effects of AZT and composition (a) were evaluated. The survival rates after 130 days are summarized in Table 1 and the chronological changes of the survival rates are shown in Fig.
1.
Table 1 Group No. of mice Alive Dead Suvival rate Control 22 8 14 36 Comp. (a) 10 3 7 30 Comp. (a) + AZT 10 8 2 80 Statistical significance between the control group and the treated group in a survival rate was evaluated at day 130 after the viral infection.
*: p=0.027, compared with control (Fisher's exact method).
As shown in Table 1 and Fig. 1, mortality of MAIDS
mice administered with AZT and composition (a) was clearly improved as compared with that of MAIDS mice administered with AZT alone.
INDUSTRIAL APPLICABILITY
As described above, the therapeutic method of the present invention provides remarkably improved therapeutic effect on AIDS patients as compared with the case in which a nucleoside-type anti-HIV agent alone is administered.
Claims (20)
1. Remedies for AIDS, which comprise as active ingredients (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of human-type tubercle bacillus and (b) a nucleoside-type anti-HIV agent.
2. The remedies according to Claim 1, wherein the composition (a) comprises a polysaccharide constituted by arabinose, mannose and glucose as primary constituent monosaccharides, and nucleic acid.
3. The remedies according to Claim 1, wherein the composition (a) comprises a polysaccharide having a molecular weight of 5 x 10 2 - 5 x 10 4 (as determined by gel filtration) and constituted by arabinose, mannose and glucose as primary constituent monosaccharides, and nucleic acid.
4. The remedies according to any of Claims 1 to 3, wherein the tubercle bacillus is human-type tubercle bacillus.
5. The remedies according to any of Claims 1 to 4, wherein the tubercle bacillus is an Aoyama B strain.
6. The remedies according to any of Claims 1 to 5, wherein the nucleoside-type anti-HIV agent (b) is selected from the group consisting of Zidovudine (Azidothymidine, AZT), Didanosine (ddI), Zalcitabin (ddC), Stavudine (d4T) and Lamivudime (3TC).
7. Enhancer drugs for improving the therapeutic effect of a nucleoside-type anti-HIV agent on AIDS, which comprises as active ingredients (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle.
8. Use of (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of tubercle bacillus and (b) a nucleoside-type anti-HIV
agent, for the manufacture of remedies for AIDS.
agent, for the manufacture of remedies for AIDS.
9. The use according to Claim 8, wherein the composition (a) comprises a polysaccharide constituted by arabinose, mannose and glucose as primary constituent monosaccharides, and nucleic acid.
10. The use according to Claim 8, wherein the composition (a) comprises a polysaccharide having a molecular weight of 5 x 10 2 - 5 x 10 9 (as determined by gel filtration) and constituted by arabinose, mannose and glucose as primary constituent monosaccharides, and nucleic acid.
11. The use according to any of Claims 8 to 10, wherein the tubercle bacillus is human-type tubercle bacillus.
12. The use according to any of Claims 8 to 11, wherein the tubercle bacillus is an Aoyama B strain.
13. The use according to any of Claims 8 to 12, wherein the nucleoside-type anti-HIV agent (b) is selected from the group consisting of Zidovudine (Azidothymidine, AZT), Didanosine (ddI), Zalcitabin (ddC), Stavudine (d4T) and Lamivudime (3TC).
14. Use of (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of human-type tubercle bacillus, for the manufacture of enhancer drugs for improving the therapeutic effect of a nucleoside-type anti-HIV agent on AIDS.
15. A method for treating AIDS, which method comprises administering to an HIV-infected patient (a) a composition containing as the primary component a polysaccharide derived from a hot water extract of human-type tubercle bacillus and (b) a nucleoside-type anti-HIV agent.
16. The method according to Claim 15, wherein the composition (a) comprises a polysaccharide constituted by arabinose, mannose and glucose as primary constituent monosaccharides, and nucleic acid.
17. The method according to Claim 15, wherein the composition (a) comprises a polysaccharide having a molecular weight of 5 x 10 2 - 5 x 10 4 (as determined by gel filtration) and constituted by arabinose, mannose and glucose as primary constituent monosaccharides, and nucleic acid.
18. The method according to any of Claims 15 to 17, wherein the tubercle bacillus is human-type tubercle bacillus.
19. The method according to any of Claims 15 to 17, wherein the tubercle bacillus is an Aoyama B strain.
20. The method according to any of Claims 15 to 19, wherein the nucleoside-type anti-HIV agent (b) is selected from the group consisting of Zidovudine (Azidothymidine, AZT), Didanosine (ddI), Zalcitabin (ddC), Stavudine (d4T) and Lamivudime (3TC).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/038,041 US6015796A (en) | 1998-03-11 | 1998-03-11 | Method for treating AIDS |
| US09/038,041 | 1998-03-11 | ||
| PCT/JP1999/001182 WO1999045917A1 (en) | 1998-03-11 | 1999-03-11 | Remedies for aids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2323015A1 true CA2323015A1 (en) | 1999-09-16 |
Family
ID=21897785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002323015A Abandoned CA2323015A1 (en) | 1998-03-11 | 1999-03-11 | Remedies for aids |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6015796A (en) |
| EP (1) | EP1062947A1 (en) |
| KR (1) | KR20010040752A (en) |
| AU (1) | AU737861B2 (en) |
| CA (1) | CA2323015A1 (en) |
| WO (1) | WO1999045917A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6020325A (en) * | 1999-03-09 | 2000-02-01 | Zeria Pharmaceutical Co., Ltd. | Method for inhibiting replication of HIV |
| ATE354855T1 (en) * | 2000-10-13 | 2007-03-15 | Lapp Insulator Gmbh | PRODUCTION OF COMPOSITE INSULATORS BY INJECTING INDIVIDUAL SHIELDS TO A STRUCTURE |
| JP2015157763A (en) * | 2012-05-28 | 2015-09-03 | エヌエーアイ株式会社 | Therapeutic and preventive agent for dementia |
| JPWO2022176068A1 (en) * | 2021-02-17 | 2022-08-25 | ||
| JPWO2022176920A1 (en) * | 2021-02-17 | 2022-08-25 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5833240B2 (en) * | 1976-11-10 | 1983-07-18 | 呉羽化学工業株式会社 | Protein polysaccharide APS |
| JPS59161320A (en) * | 1983-03-04 | 1984-09-12 | Maruyama Chisato | Lipopolysaccharide and its preparation |
| JPH0816118B2 (en) * | 1988-02-03 | 1996-02-21 | 呉羽化学工業株式会社 | Antiviral agent |
| US5521161A (en) * | 1993-12-20 | 1996-05-28 | Compagnie De Developpment Aguettant S.A. | Method of treating HIV in humans by administration of ddI and hydroxycarbamide |
| FR2715660A1 (en) * | 1994-01-28 | 1995-08-04 | Centre Nat Rech Scient | Organophosphorus activating compounds of Tgammadelta lymphocytes, process for preparing and / or isolating and / or characterizing these compounds, compositions and pharmaceutical uses. |
| JP3586924B2 (en) * | 1994-04-18 | 2004-11-10 | 味の素株式会社 | Method for producing 5-methyluridine |
| JPH08208502A (en) * | 1995-02-06 | 1996-08-13 | Tsumura & Co | Medicine for incrasing effect of aids virus medicine |
-
1998
- 1998-03-11 US US09/038,041 patent/US6015796A/en not_active Expired - Fee Related
-
1999
- 1999-03-11 KR KR1020007008640A patent/KR20010040752A/en not_active Application Discontinuation
- 1999-03-11 EP EP99939160A patent/EP1062947A1/en not_active Withdrawn
- 1999-03-11 CA CA002323015A patent/CA2323015A1/en not_active Abandoned
- 1999-03-11 WO PCT/JP1999/001182 patent/WO1999045917A1/en not_active Application Discontinuation
- 1999-03-11 AU AU32763/99A patent/AU737861B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU737861B2 (en) | 2001-08-30 |
| WO1999045917A1 (en) | 1999-09-16 |
| US6015796A (en) | 2000-01-18 |
| KR20010040752A (en) | 2001-05-15 |
| AU3276399A (en) | 1999-09-27 |
| EP1062947A1 (en) | 2000-12-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |